1. Field of the Invention
This invention relates to compositions for calming and reducing anxiety in humans and animals and, more particularly, to novel compositions of phenolic and indoleamine-like compounds obtainable in concentrations and amounts suitable for animal and human use derived, isolated, and/or extracted from certain botanicals or from chemical synthesis, together with methods for using, producing, and harvesting the same for use in calming and/or reducing anxiety in humans and animals suffering from anxiety disorders and related behaviors or during periods of stress, illness, or injury.
2. The Background Art
An estimated 35-40 million living Americans will suffer major depressive episodes, and many more will experience lesser bouts. Of the approximately 17.5 million Americans with ongoing depressions, about 9.2 million are at a clinically debilitating level. Clinical depression is characterized by a list of symptoms that last over a long time span. As appreciated by those skilled in the art, depression is a serious problem that is generally initiated or caused by outside stressors. As stresses escalate or persist, a chemical imbalance of the body usually results.
Clinical depression can be very debilitating both physically and mentally and even lead to death by means of suicide. Lost productivity and relationship problems may be consequences of lesser depressions. Presently, antidepressant medications are the cornerstones of treating depression, especially those that are at least moderately severe. Although depressed individuals and animals tend to improve when treated with antidepressants, many do not respond to the first antidepressant prescribed. Such individuals or animals may eventually benefit from a different antidepressant or, if sufficiently efficacious, a combination of suitable antidepressants.
Sexual dysfunction is another pervasive disorder. In the overall population, it is believed that forty-three percent (43%) of women and thirty-one percent (31%) of men between the ages of 18 and 59 experience sexual dysfunction and some repeatedly. As will be appreciated, sexual dysfunction may include, for example, a lack of interest in sex, problems with arousal, not enjoying sex, and anxiety associated with sexual performance. Indeed, feeling good in general has been found to have a significant impact on sexual function. In this regard, those people who are unhappy or depressed may be more likely to experience difficulties associated with sexual dysfunction. Arousal problems affect over 20 million American males (i.e., about 2 in 10 adult men), with such difficulties often associated with or accompanied by some sort of depression or mood disorder. Meanwhile, prescription antidepressants have been found to actually exacerbate the situation, since a frequent side effect of their use is sexual dysfunction. In fact, sexual response may actually diminish in up to seventy-five percent (75%) of prescription antidepressant users for using the same. To this end, there is a need for forms of treatment that reduce depression or otherwise better mood with an accompanying enhancement of sexual response, arousal or desire or, in the alternative, do not have a negative impact on a person's or animal's sexual function.
Prior work by those skilled in the art in connection with the compounds of the present invention have been primarily focused on 6-methoxy-2,3-benzoxazolinone (6-MBOA). For example, the role of 6-MBOA in strengthening the resistance of monocotyledonous plants against a wide range of insect pests has been much studied. It has been further proven that 6-MBOA and its chemical precursors may also have allelopathic properties that may inhibit root and shoot growth in competing species. Moreover, it has been found that 6-MBOA may have antimicrobial properties, wherein 6-MBOA appears constitutively during early stages of growth, localized in those tissues most exposed to microbial and insect attack.
It had been long suspected that compounds in plants affect the seasonal reproductive output of wild rodents. In 1981, 6-MBOA became the first naturally occurring compound in a plant that was verified as impacting seasonal reproductive cycling. As readily known, 6-MBOA may be found in varying concentrations in monocotyledonous plants. Since then, a substantial body of work has accumulated on 6-MBOA as an initiator of seasonal breeding and an effector of population size for many rodents and a few birds. Compounds related to and possibly co-occurring with 6-MBOA remain generally unexplored in this regard.
6-MBOA may be passed from adult females to offspring during gestation and lactation, which typically results in increased growth and larger gonads in the recipient young. Juveniles rely on the interaction of maternal photoperiod history and 6-MBOA to time the onset of growth and puberty. It has been found that adult animals that are fed a diet containing 6-MBOA produce more female progeny. Similarly, when 6-MBOA is fed to pregnant females, gonadal development in the male offspring is usually enhanced.
In rodents, it has been found that the inhibitory effects of melatonin on growth and reproduction are blocked partially by 6-MBOA (Gower et al., “Reproductive responses of male Microtus montanus to photo period, melatonin, and 6-MBOA”, Journal of Pineal Research, 8: 297-312, 1990). As further shown by those skilled in the art, 6-MBOA may obstruct melatonin at the melatonin receptors or act independently to check melatonin action (Sweat et al., “Uterotropic 6-methoxybenzoxazolinone is an adrenergic agonist and melatonin analog,” Molecular and Cellular Endocrinology, 57:131-138, 1988).
The high melatonin levels induced by 6-MBOA may also cause desensitization of melatonin receptors (Daya et al., “Effect of 6-methoxy-2-benzoxazolinone on the activities of rat pineal N-acetyltransferase and hydroxyindole-O-methyltransferase and on melatonin production,” Journal of Pineal Research, 8:57-66, 1990), but not for all rodents (Anderson et al., “Effects of melatonin and 6-methoxybenzoxazolinone on photoperiodic control of testis size in adult male golden hamsters,” Journal of Pineal Research, 5:351-65, 1988).
Further findings of those skilled in the art suggest that 6-MBOA stimulates rather than inhibits melatonin biosynthesis and does not prevent stimulation of melatonin synthesis by norepinephrine (Yuwiler et al., “Effects of 6-methoxy-2-benzoxazolinone on the pineal melatonin generating system,” J. Pharmacol. Exp. Ther. 233:45-50, 1985). Moreover, 6-MBOA may act at both the alpha-(α) and beta-(β) adrenergic receptors (Daya et al., “Effect of 6-methoxy-2-benzoxazolinone on the activities of rat pineal N-acetyltransferase and hydroxyindole-O-methyltransferase and on melatonin production,” Journal of Pineal Research, 8:57-66, 1990), and may stimulate adenylcyclase (i.e., adenylate cyclase) activity in the pineal, hypothalamus and pituitary glands (Sweat et al., “Uterotropic 6-methoxy-benzoxazolinone is an adrenergic agonist and melatonin analog,” Molecular and Cellular Endocrinology, 57:131-138, 1988).
As appreciated, certain responses to 6-MBOA, like uterine hypertrophy, can be duplicated with estrogen, but 6-MBOA is not an estrogenic compound (Gower, “Endocrine effects of the naturally occurring reproductive stimulant, 6-methoxy-benzoxazolinone,” Ph.D. Thesis, University of Utah, Salt Lake City, Utah, 1990). Also, 6-MBOA may increase the rate of synthesis of follicle stimulating hormone (Butterstein et al., “The plant metabolite 6-methoxybenzoxazolinone interacts with follicle-stimulating hormone to enhance ovarian growth,” Biology of Reproduction, 39:465-71, 1988) and pituitary prolactin (Vaughan et al., “Hormonal consequences of subcutaneous 6-methoxy-2-benzoxazolinone pellets or injections in prepubertal male and female rats,” Journal of Reproduction and Fertility, 83:859-66, 1988). In addition, hypothalamic luteinizing hormone-releasing hormone contents and pituitary gland weights are greater for at least one rodent species implanted with capsules containing 6-MBOA (Urbanski et al., “Influence of photoperiod and 6-methoxybenzoxazolinone on the reproductive axis of inbred LSH/Ss Lak male hamsters.” Journal of Reproduction and Fertility, 90:157-163, 1990).
The inventors of the present invention recognized that 6-MBOA and the indoleamine, melatonin, share a structural similarity. However, melatonin exacerbates symptoms of dysphoria in depressed people. 6-MBOA, as a melatonin agonist, could prove contrary in this regard and actually improve mood. Yet, the inventors are not aware of any prior art that has explored or suggested the use of 6-MBOA or related compounds as having psychotropic effects in humans, particularly with respect to depression or bettering mood. An object of the present invention is to develop therapies for depression and sexual dysfunction entailing use of compounds belonging to related chemical families, of which 6-MBOA is a member. Pursuant to this end, a further object is to develop methods for extracting, deriving, and/or isolating said compounds from plant and animal sources in amounts suitable for human therapeutic use.
In addition to the effects of stress on depression and mood disorders, as well as sexual performance (i.e., desire, arousal and performance), as outlined hereinabove, those skilled in the art may also appreciate the multiple effects of stress on the immune systems and anxiety levels in animals and humans. For example, animals may be at risk for immune dysfunction related to stress which may manifest as increased infections, morbidity, and mortality associated with shipping stress, surgery, weaning, performance or training, crowding, and/or mixing with unfamiliar animals. The costs of such immune impairment to the livestock and other food animal industries may be significant and is estimated at over $1 billion per year in the United States alone.
Stress in animals and humans may be due to physical, chemical or electromagnetic challenge; illness; injury; and/or psychologic factors. Typically, these factors induce physiological adaption within the body of the stressed animal or human. Adaption may manifest in a plurality of responses. Stress-induced changes in hormone production may include higher levels of corticosterone, an immunosuppressive hormone. Stress and anxiety induced neuroendocrine responses may be associated with changes in immune system function including alterations in levels of pro-inflammatory cytokines. These stress-induced responses may, accordingly, result in an increased susceptibility to viral and bacterial infection, and a greater possibility of complications associated with cytokine abnormalities and inflammatory processes.
Humans may demonstrate immune abnormalities that may increase the risk for infection and autoimmune reactions following a variety of stressful stimuli, including injury, surgery, infection, psychological stress, mental illness (e.g., depression), and physical challenges such as intense elite athlete training. The resulting complications due to immune impairment in humans may facilitate significant increased costs of medical care and lost work days.
Those skilled in the art, including ethnobotanists, pharmacognosists, medicinal chemists, and certain mental health care practitioners are constantly in search of new compounds derived or isolated from plant materials that have anti-anxiety properties. For example, anti-anxiety activity has been widely associated with kava kava and commercial products containing kava kava and claiming and anti-anxiety effects are widely known.
An object of the present invention is to develop compositions and methods for calming and reducing anxiety in animals and humans entailing use of compounds belonging to related chemical families, of which 6-MBOA is a member. Pursuant to this end, a further object is to develop methods for extracting, deriving, and/or isolating said compounds from plant and animal sources in amounts suitable for human therapeutic use.
While past research by those skilled in the art has attempted to isolate, identify, and characterize new plant compounds with anti-anxiety properties, 6-MBOA has heretofore previously not been identified or evaluated for calming and anti-anxiety properties. Therefore, novel compounds derived, isolated, extracted, produced, and/or harvested from monocotyledonous plants or by chemical synthesis and methods for using the same to reduce anxiety and related pathology in animals and humans would be a significant advancement in the art. Such novel compositions and methods are disclosed and taught herein.